Epidemiological and animal studies now firmly establish that environmental exposures during eariy embryonic development play a critical role in disease susceptibility in later-life. Moreover, such exposures during gestation have been directly linked with subsequent disease formation through epigenetic mechanisms. Little research, however, has considered the combined effects of perinatal and peripubertal , exposures on life course metabolic syndrome risk and reproductive development. Utilizing an established mouse model of perinatal exposures and focusing on bisphenol A (BPA), phthalates, and lead (Pb) as representative toxicants, we focus on the influence of perinatal and peripubertal exposures on offspring metabolic status and epigenetic gene regulation. Specifically, we will investigate whether perinatal exposure to BPA/phthalates/Pb mixture results in epigenetic alterations and disrupts life course physiologic status, events that are subject to modification by diet and continued peripubertal exposure. First, capitalizing on our mouse models of physiologically relevant maternal toxicant levels, we will assess whether pregnancy and postnatal high-fat diet modifies the effects of perinatal BPA or Pb exposure on life course physiological parameters. Second, we will use sophisticated mouse phenotyping to examine the relationship of perinatal and peripubertal exposure to chemical mixtures on metabolic and reproductive status and identify key epigenetic labile genes important for metabolic homeostasis and hormonal regulation. Finally, animal models are well-poised to elucidate complex relationships among exposures, epigenetic tissue specificity, and timedependent epigenetic drift. Thus, we will conduct unbiased lineage specific whole methylome, transcriptome, and histone mark analysis at multiple time points. Results of these comprehensive studies will elucidate issues of tissue specificity and drift with age, inherent complexities in conducting epigenetic epidemiological studies. Knowledge from this project is crucial for deciphering the role of epigenetic programming by early exposures in the pathogenesis of diseases, including metabolic syndrome and reproductive success, and for the development of novel epigenetic-based diagnostic and therapeutic strategies for human diseases.